Thymic adipogenesis and age-related thymic demise

描述(申请人提供)：随着年龄的增长，胸腺产生幼稚T细胞的能力减弱，这仍然是免疫学的一个基本和令人困惑的现象，到目前为止，这是一种导致老年人免疫功能障碍的棘手的临床状况。随着年龄的增长，胸腺会经历显著的纤维化和脂肪变化，最终转化为脂肪组织。异位脂肪细胞的谱系和胸腺脂肪细胞在衰老过程中的发育机制尚不清楚。利用谱系追踪，我们的研究团队已经证明，对于T细胞发育所必需的FOXN1+胸腺上皮细胞(TECs)可以过渡和 产生胸腺成脂前体细胞。与这一新范式一致，我们最新的初步数据提供了进一步的活体证据，表明老化胸腺中的前体脂肪细胞可以通过次级间充质前体来自上皮和内皮细胞系。基于我们的新发现，这一建议的中心假设是TECs和内皮细胞的转变有助于胸腺脂肪细胞的谱系形成，并导致与年龄相关的胸腺退缩。由此推论，阻断TEC和内皮细胞的纤维化形成和促脂肪信号转导将保护胸腺不受衰老的影响。目标1中的实验将验证假设1，即随着年龄的增长，FOXN1+细胞通过上皮-间充质转化(EMT)过程向成脂前体细胞转化，产生异位胸腺脂肪细胞，并损害胸腺基质微环境。目的2将验证内皮祖细胞作为成脂前体细胞的假说2，并将揭示阻断胸腺血管周围间隙异位脂肪细胞的发育可防止胸腺衰老。目标3将验证假设3，即胸腺中与年龄相关的纤维化形成导致胸腺生成减少，并揭示将次级间充质细胞转化为脂肪细胞的机制参与了胸腺功能障碍。该研究项目的长期目标是了解导致胸腺肥胖的机制，并开发新的方法来预防或逆转与年龄相关的胸腺退化过程。

DESCRIPTION (provided by applicant): Diminished ability of thymus to produce naive T cells with progressive aging remains a fundamental and puzzling phenomenon for immunology and to-date, an intractable clinical condition that contributes to immune dysfunction in elderly. With advancing age, the thymus undergoes striking fibrotic and fatty changes that culminate in its transformation into adipose tissue. The lineage of ectopic adipocytes and the mechanism of development of thymic adipocytes during aging are not well understood. Using lineage-tracing, our research team has shown that FoxN1+ thymic epithelial cells (TECs), that are necessary for T cell development, can transition and give rise to thymic adipogenic precursors. Consistent with this new paradigm, our lates preliminary data provide further in vivo evidence that proadipogenic cells in aging thymus can originate from epithelial and endothelial lineages via a secondary mesenchymal precursor. Based on our novel findings, the central hypothesis of this proposal is that the transition of TECs and endothelial cells contribute towards the lineage of thymic adipocytes and leads to age-related thymic involution. The corollary is that blocking the fibrogenesis and pro- adipogenic signaling in TEC and endothelial lineage cells will protect against aging of thymus. Experiments in Aim 1 will test the hypothesis 1 that with advancing age transition of FoxN1+ cells into adipogenic precursors via epithelial-mesenchymal transition (EMT) process gives rise to ectopic thymic adipocytes and compromises the thymic stromal microenvironment. Aim 2 will test the hypothesis 2 that that endothelial-lineage cells serve as adipogenic progenitors and will reveal that blocking he ectopic adipocyte development in thymic perivascular space protect against thymic aging. The Aim 3 will test the hypothesis 3 that age-related fibrogenesis in thymus causes reduction in thymopoiesis and reveal that mechanisms that commit secondary mesenchymal cells into adipocytes participate in thymic dysfunction. The long-term goal of this research project is to understand the mechanisms that cause thymic adiposity and to develop new approaches to prevent or reverse the process of age-related thymic involution.